Article of manufacture



United States Patent ARTICLE OF MANUFACTURE Bruce W. Horrom, Waukegan,Ill., assigmor to Abbott Laboratories, North Chicago, Ill., acorporation of Illinois No Drawing. Application December 24, 1956 SerialNo. 630,086

8 Claims. (Cl. 167-65) This invention relates to a new article ofmanufacture and to methods of compounding and using the same. Moreparticularly, the invention relates to the compound dicyclopropylketoxime in a dosage unit form suitable for use as a muscle relaxant.

The compound dicyclopropyl ketoxime has the following structural formula1l\lr01-1 M It is a white crystalline solid material that is sparinglysoluble in water up to a level of 0.5%, and highly soluble in organicsolvents such as benzene, ether, alcohol and the like. It has a boilingpoint of 141-146" C. (60 mm.) and when recrystallized from petroleumsolvent, the solid material has a melting point of 76-77 C.

The method for preparing dicyclopropyl ketoxime has been described by H.Hart and O. E. Curtis, Jr., J.A.C.S., volume 78, page 112 (1956).

The muscle relaxant properties refer to relief of skeletal muscletension and spasms by interrupting synaptic transmissions at variouslevels of the central nervous cord rather than interrupting peripheralnervous impulses at the myoneural junction of skeletal muscle, thusdistinguishing their mode of action from curare-like drugs.

It is the object of this invention to provide convenient dosage unitforms of a compound having marked muscle relaxant properties, inparticular dosage unit forms of the compound dicyclopropyl ketoxime.

Another object is to prepare said dosage forms in solid and liquidcarriers suitably selected for either oral or injectable administration.

It has now been found that the compositions of this invention employingdicyclopropyl ketoxime are highly effective muscle relaxants of theinternuncial neuron depressant type. They have low toxicity and can beadministered orally in dosage units of the size, type and kind to bedescribed hereinafter.

The effective clinical dose of dicyclopropyl ketoxime for adults rangesfrom about 100 mg. per day upwardly. In children the dosage rangescorrespondingly lower according to the age and Weight of the child. Thedrug may be administered in the forms of tablets, capsules, powder or ina flavored suspension or solution. A preferred form of administration isin scored tablets each containing 10 mg. of drug, which will provide theminimum dose for children when broken in half, and when taken inmultiples will provide amounts up to the maximum dose.

In one of the preferred compositions the active ingredient,dicyclopropyl ketoxime, may be incorporated into tablets by utilizingstandard ingredients and steps in the preparation thereof. Inparticular, solid diluents and "ice tableting adjuvants such as cornstarch, acacia, lactose, talc, stearic acid, magnesium stearate, gumsand the like may be used. Any of the tableting materials used in thepharmaceutical art may be employed where there is no incompatibilitywith the active material. Alternatively, the active material with orwithout its adjuvant materials may be placed in a soft or hard gelatincapsule and administered in capsule form.

In another embodiment of the invention a solution dose form is made.Although solubility in water is low (0.5%), a sufficient concentrationof dicyclopropyl ke toxime can be dissolved to provide a therapeuticdosage. A solution dosage form can contain from about 2 mg. per cc. (10mg. per teaspoon) to about 5 mg. per cc. of the active ingredient.Should a liquid dosage form containing a greater concentration of theactive material be desired, a suspension of dicyclopropyl ketoxime maybe prepared by compounding the active ingredient in concentration aboveabout 5 mg. per cc. of liquid with suspending agents such as acacia orcarboxymethylcellulose along with the usual flavoring materials. Such aliquid preparation is particularly suitable for children and infirmpersons who have difliculty swallowing a tablet or capsule.

The following examples illustrate preferred embodiments of the dosageforms, but it should be understood that they are not meant to restrictthe dosage forms to ingredients and proportions named therein.

EXAMPLE I Dicyclopropyl ketoxime tablets Dicyclopropyl ketoxime (1.33pounds) is mixed with 37.31 pounds of lactose and passed through a30-mesh screen. A starch paste is prepared using 1.05 pounds of cornstarch and 5.98 pounds of distilled water. The starch paste is massedwith the prior mixture and passed through a 4-mesh screen and then driedat F. for 17 hours. The dried paste is granulated and passed through a16 screen. Stearic acid (0.446 pound), corn starch (3.87 pounds) andtalc (2.036 pounds) are passed through a 40-rnesh screen and blendedwell with the granulated dicyclopropyl ketoxime, lactose and cornstarch.

The blended material is compressed into tablets each containing 10 mg.of active material.

EXAMPLE II Dicyclopropyl ketoxime in solution dose form A pharmaceuticalsolution of dicyclopropyl ketoxime is prepared by combining thefollowing ingredients:

Dicyclopropyl ketoxime gms 2.0 Sucrose gms 200.0 Glucose gms" 250.0Glycerin cc 50.0 Methyl-p-aminobenzoate -gms- 1.5 Propyl-p-aminobenzoategms 0.15 F.D. & C. orange #1 gms 0.05 Imitation orange aroma cc 0.02 Oilorange cc 0.5 Water, Ilco, q.s. cc 1000.0

The foregoing solution provides a concentration of active ingredient ata level of 2 mg. per cc. or 10 mg. per teaspoon.

The esters of p-hydroxybenzoic acid prevent fermentation and moldformation.

3 EXAMPLE n1 Dicyclopropyl ketoxime in suspension dose form Apharmaceutical suspension of dicyclopropyl ketoxime is prepared bycombining the following ingredicuts:

The foregoing suspension provides a concentration of active ingredientat a level of 10 mg. per cc. or 50 mg. per teaspoon.

While the foregoing preparations are designed for oral administration,appropriate solutions or suspensions containing dicyclopropyl ketoximemay be devised for injectable introduction into the body. The terminjectable introduction is intended to include all the routes availableto this form of dosage, namely intravenous, intramuscular andintraperitoneal. Such injectable compositions resemble the product ofExample II except that the sugars, flavors, colors and glycerin arereplaced with an equivalent amount of water.

Others may practice the invention in any of the numerous ways which willbe suggested by this disclosure to one skilled in the art. vention isconsidered to be a part hereof provided it falls within the scope of theappended claims.

I claim:

1. An article of manufacture characterized by skeletal muscle relaxantactivity comprising at least about 10 mg. of dicyclopropyl ketoxime anda non-toxic pharmaceutical carrier.

All such practice of the in- 2. An article of manufacture characterizedby skeletal muscle relaxant activity comprising at least about 10 mg. ofdicyclopropyl ketoxime and a non-toxic solid pharmaceutical carrier indosage unit form.

3. An article of manufacture characterized by skeletal muscle relaxantactivity comprising an aqueous liquid pharmaceutical carrier containingat least about 2 mg. of dicyclopropyl ketoxime per cc. of liquid.

4. A composition characterized by skeletal muscle relaxant activitycomprising an aqueous pharmaceutical suspension including a non-toxicsuspending agent and at least about 5 mg. per cc. of dicyclopropylketoxime.

5. The method of causing muscle relaxation in persons subject toexcessive skeletal muscle tension which comprises administering to thehuman host a non-toxic composition containing at least about 10 mg. ofdicyclopropyl ketoxime.

6. The method of causing skeletal muscle relaxation in a living hostafilicted with excessive muscle tension which comprises administeringorally to the living host a non-toxic composition comprising at leastabout 10 mg. of dicyclopropyl ketoxime and a pharmaceutical carrier.

7. The method of causing skeletal muscle relaxation in a living hostafilicted with excessive tension which comprises administering byinjection a non-toxic pharmaceutical solution containing at least about2 mg./cc. of dicyclopropyl ketoxime.

8. The method of causing skeletal muscle relaxation in a living hostafilicted with excessive muscle tension which comprises administeringorally to the living host a non-toxic, aqueous pharmaceutical suspensioncontaining at least about 5 mg./cc. of dicyclopropyl ketoxime and anon-toxic suspending agent.

References Cited in the file of this patent Colman et al.: Ber. Deut.Chem, vol. 19 (II), 1896, pp. 3113-3114.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non2,916,417 December 8, 1959 Bruce W, Horrom appears in the printedspecification It is hereby certified that error correct-ion and that thesaid Letters of the above numbered patent requiring Patent should readas corrected below.

Column 4, line 24, for excessive tension" read excessive' muscle tensionSigned and sealed this 24th day of May 1960,

(SEAL) Attest:

KARL AXLINE Attesting @mcer ROBERT C. WATSON Commissioner of Patents

1. AN ARTICLE OF MANUFACTURE CHARACTERIZED BY SKELETAL MUSCLE RELAXANTACTIVITY COMPRISING AT LEAST ABOUT 10 MG. OF DICYCLOPROPYL KETOXIME ANDA NON-TOXIC PHARMACEUTICAL CARRIER.